In our studies of the psychoactive properties of thyrotropin releasing hormone (TRH) in rabbits, we made several important observations which require further investigation. These include: (1) the extremely potent analeptic property of TRH against various CNS depressants; (2) the ability of TRH to exert this effect when administered intracerebrally into various areas of the brain; (3) the ability of cyclic AMP analogs to exert TRH-like effects, and (4) the ability of centrally administered TRH and cyclic nucleotides to produce marked increases in gastrointestinal motility. We plan to characterize and to determine the mechanisms of these several actions of TRH and the cyclic nucleotides. TRH or the cyclic nucleotides will be administered either intraventricularly or intracerebrally by techniques we are currently employing and which have been published in the literature. Analeptic activity is represented by a shortened recovery time of the righting reflex when animals receiving depressants are pre- or posttreated with TRH or the cyclic AMP analogs. The possible role of cyclic nucleotides in the TRH effects will be investigated employing in vitro techniques in which cyclic AMP or GMP will be assayed after incubating brain slices with TRH. In vivo relationships will be based on the phosphodiesterase inhibitors potentiating the TRH and cyclic AMP analog-induced analeptic effects. Electrophysiological correlates of the analeptic and behavioral effects of TRH and the cyclic nucleotides will be determined by analysis of EEG activities. The gastrointestinal effects of centrally administered TRH and cyclic nucleotides will be carried out in anesthetized rabbits. GI motility will be recorded via an extraluminal strain gauge and onto a polygraph. Various antagonists will be employed in order to determine whether the effects are mediated via nervous or humoral mechanisms.